Department of Pharmaceutical Chemistry, University of California San Francisco, San Francisco, CA 94158, USA; College of Pharmaceutical Sciences, Southwest University, Chongqing 400716, China.
Department of Biology, Stanford University, Stanford, CA 94305, USA; Laboratory of Virus Control, Center for Infectious Disease Education and Research, Osaka University, Osaka, Japan; Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
Cell Chem Biol. 2022 Aug 18;29(8):1303-1316.e3. doi: 10.1016/j.chembiol.2022.06.006. Epub 2022 Jul 12.
The potential of small molecules to localize within subcellular compartments is rarely explored. To probe this question, we measured the localization of Hsp70 inhibitors using fluorescence microscopy. We found that even closely related analogs had dramatically different distributions, with some residing predominantly in the mitochondria and others in the ER. CRISPRi screens supported this idea, showing that different compounds had distinct chemogenetic interactions with Hsp70s of the ER (HSPA5/BiP) and mitochondria (HSPA9/mortalin) and their co-chaperones. Moreover, localization seemed to determine function, even for molecules with conserved binding sites. Compounds with distinct partitioning have distinct anti-proliferative activity in breast cancer cells compared with anti-viral activity in cellular models of Dengue virus replication, likely because different sets of Hsp70s are required in these processes. These findings highlight the contributions of subcellular partitioning and chemogenetic interactions to small molecule activity, features that are rarely explored during medicinal chemistry campaigns.
小分子在亚细胞隔室中定位的潜力很少被探索。为了探究这个问题，我们使用荧光显微镜测量了 Hsp70 抑制剂的定位。我们发现，即使是密切相关的类似物也有明显不同的分布，有些主要位于线粒体，有些则位于内质网。CRISPRi 筛选支持了这一观点，表明不同的化合物与内质网（HSPA5/BiP 和 HSPA9/mortalin）和线粒体（HSPA9/mortalin）及其共伴侣的 Hsp70 具有不同的化学遗传学相互作用。此外，定位似乎决定了功能，即使对于具有保守结合位点的分子也是如此。与登革热病毒复制的细胞模型中的抗病毒活性相比，具有不同分配的化合物在乳腺癌细胞中具有不同的抗增殖活性，这可能是因为这些过程需要不同的 Hsp70 集合。这些发现强调了亚细胞分区和化学遗传学相互作用对小分子活性的贡献，这些特征在药物化学研究中很少被探索。
